Method for the production of a biocompatible polymer-ceramic composite material with a predetermined porosity

ABSTRACT

Method for the production of a biocompatible polymer-ceramic composite material with a predetermined porosity, designed and determined a priori, which includes a first phase (a) of the production of a suspension of a bioceramic material in distilled water, a second phase (b) in the which a compact of the bioceramic material containing a desired quantity of water is obtained from the suspension, and a third phase (c) in the which the compact is mixed with a polymeric material and/or a liquid monomer.

TECHNICAL FIELD

[0001] The present invention relates to a method used to obtain abiocompatible polymer-ceramic composite material of a predeterminedporosity, designed and determined a priori.

BACKGROUND ART

[0002] It has been known for some time that polymethyl methacrylate(PMMA)/calcium phosphate type porous composites may be employed in aseries of applications, such as the filling of bone voids or as drugdelivery systems for the controlled release of pharmaceuticals. In fact,these composites display a proven biocompatibility, and at the same timethey succeed in wedding the mechanical resistance characteristicsinherent in the polymeric materials such as PMMA with thebio-reabsorption characteristics of bioceramic materials such as calciumphosphate.

[0003] A determining aspect of such polymer-ceramic composite materialsis porosity, which can be a deciding factor both for the mechanicalcharacteristics and for the functional characteristics of the compositematerials themselves. In fact, porosity allows the composite material tohost staminal cells, proteins that stimulate the colonisation of thepatient's staminal cells, antibiotics, growth elements, and otherbioactive substances that in general promote the processes ofattachment, osteointegration and/or reabsorption of the compositematerial.

[0004] Further, designing the porosity is particularly important, sincethe pores must assume specific characteristics both in shape and size asa function of the various applications of the material. In fact, therole of porosity and the degree of interconnection between the pores hasbeen recognised as an important parameter both for the reconstruction ofbone tissue inside the implanted polymer matrix and for the releaseperiods of any pharmaceuticals inserted in the composite material.

[0005] Generally, biopolymeric porous materials are created usingfoaming agents or by inserting in the polymer matrix powders ofparticles that can be dissolved at a later stage, as, for example,soluble salts or gelatin microspheres.

[0006] The solid particles destined to create the porosity can beintroduced in the melted polymer, in the monomer or mixed with the solidprepolymer before the polymerisation or reticulation reaction. Duringthis phase, difficulties may arise due to the possibility that a fewparticles can remain isolated and therefore do not contribute to theformation of porosity, or that the area of contact between two particlescan be very small. In such cases, the periods for the removal of thesolid increase, the diffusion of bodily fluids is inhibited and a largefraction of porosity can therefore prove useless from the point of viewof cellular colonisation. Porosity created using foaming agents can alsoentail the same type of difficulty, with the formation of a largefraction of cells that are closed or only virtually connected throughfractures in the surfaces that connect one cell to another.

[0007] With the aim of resolving these difficulties, the use ofbiocompatible and bioabsorbable liquids has been proposed. Inparticular, an especially effective method according to U.S. Pat. No.4,373,217 is the advance treatment of the ceramic material powders withthese liquids, aiming to fill the porosity, at least in part, in orderto avoid it becoming filled with monomer during the initial phases ofpolymerisation, consequently impeding the subsequent dissolution of theceramic material and therefore the creation of the desired porosity inthe final composite. Further, the article “Use of α-tricalcium phosphate(TPC) . . . ” by D. T. Beruto, R, Botter in the Journal of BiomedicalMaterials Research 49, 498-505, 2000, discloses the use of distilledwater to create aqueous dispersions of the bioceramic material utilised,which are subsequently mixed with the polymeric material and with liquidmonomer. The use of these dispersions, beyond avoiding the difficultiesexplained above and guaranteeing the generation of good porosity, alsoprevents the bioceramic materials used, as for example calciumphosphate, from absorbing part of the liquid monomer and removing itfrom polymerisation with the successive risk that it be released itselfin the patient's circulatory system. The liquids utilised, in fact,being miscible with the bioceramic material and non-miscible with themonomer or with the polymer used, impede the contact of the latter withthe bioceramic material itself.

[0008] The techniques utilised up to now, which call for the creation ofaqueous dispersions of the bioceramic material, notwithstanding the factthat they succeed in resolving the difficulties described above, arenonetheless incapable of allowing for the design and achievement of afinal porosity of the predetermined composite.

DISCLOSURE OF INVENTION

[0009] The aim of the present invention is to realise a method for theproduction of a polymer-ceramic composite material using which it willbe possible to predict and design the porosity of the final compositematerial.

[0010] According to the invention therefore, a method is created toobtain a biocompatible polymer-ceramic composite material of apredetermined porosity, said method comprising a first phase (a) of theproduction of a suspension of bioceramic material in distilled water,and is characterised by the fact that it also comprises a second phase(b) in which a compact of said bioceramic material containing a desiredquantity of water is obtained from the suspension; said compact is thenmixed in a third phase (c) with a polymeric material and/or with aliquid monomer.

[0011] Preferably, the desired quantity of water is calculated on thebasis of a combination of a calibration curve of the water contained ina compact of bioceramic material as a function of the different level ofcompaction used to create the compact, and from a calibration curve ofthe porosity of a polymer-ceramic composite as a function of thequantity of water contained in the compact used in creating thepolymer-ceramic composite itself.

[0012] Preferably, the compact is obtained using a sedimentation incentrifuge operation.

[0013] Preferably, the polymeric material utilised is polymethylmethacrylate, the liquid monomer is methyl methacrylate and a suspensionof a prepolymer in the monomer is prepared in advance, which is thenmixed with the compact containing the predetermined quantity of water.

[0014] Preferably, the bioceramic material is constituted ofcalcium-deficient hydroxyapatite or tricalcic-phosphate α.

[0015] Preferably the bioceramic material should be used with a definedgranulometry. For instance, diameters between 1 μm and 200 μm can beused.

[0016] More Preferably the diameter range for the selected powder can becomprised between 1 μm and 10 μm or 10 μm and 50 μm or 50 μm and 100 μm.

[0017] According to a preferred embodiment of the invention, thepreparation of the tricalcic-phosphate α comprises a final rapid coolingphase and a sieving phase, possibly after grinding, in order to collectparticles of irregular shape, approximately ranging between 1 μm and 10μm in size.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Further characteristics of the invention will be apparent fromthe following description of a few examples, provided for illustrativepurposes only and that are not limitative, and which will be describedwith reference to the attached figures, among others, in which:

[0019]FIG. 1 is a graphic that shows the trend of the total volume WR ofwater retained by the compact at the end of the sedimentation trials asa function of the centrifugal acceleration used;

[0020]FIG. 2 is a graphic that represents the trend of the volume WB ofbonded water retained by the compact at the end of the sedimentationtrials, as a function of the centrifugal acceleration used; and

[0021]FIG. 3 is a graphic which represents the trend of the porosity ofthe polymer-ceramic composite as a function of the water retained by thecompact used in the production of the composite itself.

[0022]FIGS. 4 and 5 are comparative graphics representing thequantitative release of an antibiotic from composite PMMA/α-TPCsedimented and centrifuged;

[0023]FIG. 6 shows the imbibition rate of water by Wicking Techniquecomposite PMMA/α-TPC;

[0024]FIGS. 7 and 8 shows the pores diameters and volumes for compositePMMA/α-TPC obtained according to the invention.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES

[0025] Two series of composites, A and B, were prepared, which aredistinguished from each other by the use of two different bioceramicmaterials with the aim of highlighting how the design of the porosityalso depends on the type of bioceramic material utilised. Specifically,the series of composites indicated by the letter A calls for the use oftricalcic-phosphate α (α-TCP), while the series of composites indicatedwith a B calls for the use of calcium-deficient hydroxyapatite (CDHA).

[0026] In particular, in the examples shown below, the design andprediction of the porosity of the biocompatible polymer-ceramiccomposite material was obtained using a method including the followingphases:

[0027] (a′) producing a suspension of a bioceramic material, with aselected granulometry, in distilled water;

[0028] (b′) starting from identical volumetric quantities of initialsuspension, obtaining from the suspension a series of compacts of thebioceramic material containing different quantities of water;

[0029] (c′) mixing each of the compacts thus obtained with an identicalquantity of a polymeric material and/or a liquid monomer in order toobtain a porous geometric solid of pre-defined dimensions;

[0030] (d′) for each compact, calculating the porosity of the solidobtained from it; and

[0031] (e′) correlating the porosity with the residual water content ofthe compact.

Example 1

[0032] Series of Composites A

Example 1a

[0033] Preparation of the Compacts

[0034] An inorganic tricalcic-phosphate salt α (α-TCP) was preparedusing a reaction in the solid state between anhydrous CaCO3 and CaHPO4.After mixing, the dibasic calcium phosphate powders were heated in amuffle kiln to 1573 K and at the end of the reaction were rapidly cooledin order to stabilize the α phase. After cooling, the powder was sievedusing a 60 mesh sieve, and the fraction of powder that passed throughthe sieve was analyzed with X-ray diffraction, confirming the αstructure of the powder. The average size of the grains wasapproximately 10 micron.

[0035] The inorganic salt α-TCP was dispersed in the aqueous phase witha solid phase volumetric concentration equal to 10%. From thedispersions thus obtained, a total volume equal to 12.7 cm³ wasextracted. This volume was treated in a centrifuge and subjected for apre-defined period of 15 minutes to a value of acceleration (Xg). Thesame procedure was repeated various times, subjecting the variousdispersions obtained to various values of acceleration (Xg). At the endof each centrifugation period, a “compact” and an aqueous phase wereobtained. For each compact obtained, the aqueous phase was separatedfrom the compact and the residual water content of the compact wasdetermined by weight. FIG. 1 shows the water content WR (expressed incm³/grams of dry powder) remaining in the various compacts obtained fordifferent values of Xg.

[0036] The water content WR is formed by water still relatively freebetween the cracks in the grains and by water bonded by capillary andsuperficial forces to the inorganic matrix. According to this invention,the major datum in predicting the final porosity of the composite isnonetheless not total water WR, but water WB that is bonded by forces ofvarious natures to the ceramic matrix. This quantity is defined by:

WB=WR×p 1  (1)

[0037] where, for every Xg, WR is the total water inside the compact, WBis the bonded water and p1 is the probability that the water is bonded.This probability is complementary to the probability of finding freewater. The fraction of free water inside each compact thereforerepresents that part of the water that is susceptible to leak from theceramic matrix under mild force. When a specific compact, obtained bytreating the dispersion to an Xg acceleration, is subjected to a furtherforce of dXg, the first water to exit the ceramic matrix will be theleast bonded portion. An index of this quantity is given by the value ofthe derivative of the curve in FIG. 3 calculated for each experimentalabscissa Xg. Therefore, a reasonable formula to use in calculating WBis:

WB=WR×[1−k(dWB/dXg)]  (2)

[0038] where k is a parameter chosen as a function of the dispersion ofthe experimental data in order to optimize the linearity of therelation.

[0039]FIG. 2 illustrates the results of the calculations performed asabove on the basis of the experimental results of FIG. 1, in order toevaluate the bonded water content WB corresponding to each experimentalcontent WR.

Example 1b

[0040] Preparation of the Composites

[0041] The composites (PMMA/phosphate) were produced usingpre-polymerized PMMA and monomer (MMA) powders currently on themarket-such as the type used as orthopaedic cement-utilising awell-known methodology, which is summarized below.

[0042] 1.33 g of monomer (MMA) were placed in a glass beaker, and tothis 4 g of PMMA were added in a single solution. After approximately 10seconds of shaking, the mixture achieved a soft, runny and homogenousconsistency. A compact prepared in example 1a was added to thesuspension. The resulting composite paste was rendered homogeneous byrepeatedly folding the contents of the beaker back into itself forapproximately 40 seconds. At the end of this operation, the content wasextracted and formed between two flat plates of glass to a thickness ofapproximately 4 mm. After an hour at room temperature, the hardenedcomposite was dried in an oven at 60° C. for eight hours, andsubsequently was cut into regular parallelepiped shapes. Using the sameprocedure, various composites obtained from the different compactsprepared in example la were produced, as shown in Table 1, which alsoshows the amounts of additives (known) utilised to optimize thepolymerisation reaction.

[0043] The total volume of each of the composite products was measuredusing helium pycnometry after drying in a vacuum at room temperature.The internal porosity (P) was determined from the difference between theapparent volume of the trial (Va) determined geometrically and the realvolume (Vr) determined with the pycnometer.

P=Va−Vr

[0044]FIG. 3 shows the porosity (P) of the composites as a function ofthe water content (expressed in cm³/grams of powder) remaining in thevarious compacts from which the composites themselves were obtained.

Example 2

[0045] Series of Composites B

Example 2a

[0046] Preparation of the Compact

[0047] The procedure described in example 1a was repeated with thedifference that the inorganic salt used, rather than α-TCP, wascalcium-deficient hydroxyapatite (CDHA).

[0048] As in example 1a, FIG. 1 shows the water content (expressed incm³/grams of dry powder) remaining in the various compacts obtained atdifferent values of Xg, and FIG. 2 contains the corresponding values ofWB calculated as in example 1a.

Example 2b

[0049] Preparation of the Composite

[0050] The procedure described in example 1b was repeated. However, thecompacts prepared in example 1b were used. The exact amounts used interms of weight are shown in Table 1.

[0051] As for example 1b, FIG. 3 shows the porosity (P) of thecomposites as a function of the water content (expressed in cm³/grams ofpowder) remaining in the various compacts from which the compositesthemselves were obtained. TABLE 1 Component PMMA MMA 99.1% + N—N CDHA,97% + 3% dimethyl-p- αTCP benzoyl toluidine 0.9% + Dry Residual peroxideHydroquinone 75 ppm powders water Quantity 4 1.33 1.8 From 1.4 to 2

Example 3

[0052] Methodology for Predicting Porosity

[0053] A very simple procedure for obtaining a desired porosity of acomposite results from the examples given above. Once the desiredporosity and the bioceramic material to be used have been established,using an “adjustment” graphic like the one illustrated in FIG. 3calculated in advance for the appropriate bioceramic material, we lookfor the amount of water WB that the compact constituted of thebioceramic material must contain. Once the quantity of bonded water thatmust be contained in the compact has been established, we find thecentrifugal acceleration used in preparing the compact by using a secondcorresponding adjustment graphic, like that illustrated in FIG. 2.

[0054] In the end it is clear that, in the event that another method ofcompaction is used (for example press filtering, grinding, etc.), theparameter to be considered will not be the centrifugal acceleration buta parameter inherent to the method selected.

Example 4

[0055] Methodology for Choosing an Appropriate Bioceramic Composite toObtain a Certain Porosity

[0056] In order to choose the most suitable type of commercial powderfor producing a composite with PMMA of a desired porosity, we willproceed, on the basis of the previous examples, as follows:

[0057] Phase 1. Perform the calibration, in the centrifuge or with asimilar technique, of the aqueous dispersions of the commercial powdersunder analysis;

[0058] Phase 2. Construct the graphic WB vs. Xb or other variable,according to the technique used for compaction;

[0059] Phase 3. From among the initial powders, choose that which has awater content equal to WB. If it does not exist, prepare a compact,beginning with any of the powders, subjecting the initial dispersion tothe corresponding acceleration Xg according to the adjustment curve;

[0060] Phase 4. Prepare the mixture of the compact containing thedesired quantity of bonded water, the pre-polymerized PMMA powders andthe monomer according to the examples 2a and 2b.

Example 5

[0061] Preparation with Prepolymer Dispersions

[0062] Examples 2a and 2b are repeated using a variation of the methoddescribed, consisting in pre-mixing the PMMA prepolymer powder with themonomer to obtain a concentrated polydispersed suspension of sphericalPMMA particles with an average diameter of between 15 and 40 microns andan average molecular weight of between 250,000 and 350,000 uma in ahydrophobic liquid consisting predominantly of MMA monomer. Further, weuse compacts obtained by starting with bioceramic component powders withaverage granulometry of 10 microns that are obtained by grinding initialpowders with higher granulometry, between 30 and 45 microns.

Example 6

[0063] Antibiotic Release from Preparation with Prepolymer Dispersions

[0064] 2 Mixtures with the same procedure described in example 5 havebeen prepared. α-TCP is added in different amounts (28% and 31% w/wpowder component).

[0065] Either sedimentation or centrifugation is applied.

[0066] 4 different types of specimen are obtained:

[0067] 28% (α-TCP Sedimented, 28% α-TCP centrifuged; 31% α-TCPSedimented, 31% α-TCP centrifuged.

[0068] The specimen are dried for two hours at 90° C. Once dried thespecimens are weighted and then immersed in an antibiotic solution (2.5%w/w gentamicin/water) for 30 mins.

[0069] The specimen are newly weighted to measure the amount of solutionloaded.

[0070] Each specimen is placed in a different container with a knownamount of sterile saline solution.

[0071] Takings of the saline solution are made at definite times. Aftereach taking the saline solution is refreshed with new one.

[0072] The takings are then checked for antibiotic release using theAgar-well diffusion method.

[0073] The results show clearly that centrifugation permits to controlthe kinetics of release (FIG. 4); the amount of α-TCP instead influencesthe absolute value of antibiotic solution release (FIG. 5).

Example 7

[0074] Qualitative Control of Pore Dimensions

[0075] Mixtures with the same procedure described in example 6 have beenprepared.

[0076] 4 different types of specimen are obtained.

[0077] 28% α-TCP Sedimented, 28% α-TCP centrifuged; 31% α-TCPSedimented, 31% α-TCP centrifuged.

[0078] The specimen are dried for two hours at 90° C. Once dried thespecimens are weighted and then immersed in mercury for porosimetrydetermination.

[0079] The results show that the dimensions of pores are for everymixtures comprised between 2 μm and 10 μm, with a maximum rangingbetween 3 μm and 5 μm. The granulometry of α-TCP (average 10 μm)influences the dimension of the pores in the matrix FIG. 7.

Example 8

[0080] Control of the Imbibition Properties for Preparation withPrepolymer Dispersions

[0081] Mixtures with the same procedure described in example 6 have beenprepared.

[0082] 4 different types of specimen are obtained.

[0083] 28% α-TCP Sedimented, 28% α-TCP centrifuged; 31% α-TCPSedimented, 31% α-TCP centrifuged.

[0084] The specimen are dried for two hours at 90° C. Once dried thespecimens are weighted and then partially immersed in distilled waterfor dynamic weight determination. The “Wicking technique” is applied.

[0085] The results presented in FIG. 6 show that the amount of α-TCPaffects the absolute value of the water absorbed by the specimen. Thecentrifugation affects the speed of absorption.

Example 9

[0086] Quantitative Control of Porosity

[0087] Mixtures with the same procedure described in example 6 have beenprepared.

[0088] 4 different types of specimen are obtained.

[0089] 28% α-TCP Sedimented, 28% α-TCP centrifuged; 31% α-TCPSedimented, 31% α-TCP centrifuged.

[0090] The specimen are dried for two hours at 90° C. Once dried thespecimen are weighted and then immersed in mercury for porosimetrydetermination.

[0091] The results presented in FIG. 8 show that the volume of mercuryforced in the material is directly dependent on the α-TCP content andinversely dependent on centrifugation.

[0092] The results achieved are similar to the previous results, but thecomposites obtained also display a better interconnection in theporosity achieved, as evidenced by comparative experimentation with thecomposites obtained in examples 2a and 2b, performed using the “Wicking”methodology (Z. Li et al. “Wicking technique for determination of poresize in ceramic material”, J.Am.Ceram. Soc. 77, 2220-22(1999)).

[0093] The examples described thus illustrate that the compositematerials obtained using the methodology of this invention areespecially well-suited both for the production of temporary prostheseswith controlled release of pharmaceuticals, which can be achieved withpredetermined kinetics thanks to the possibility of determining theproduct's porosity in advance, as well as for highly osteo-conductivebone substitutes.

[0094] Further, it is evident that using these materials, other types ofapplicative products can also be produced, in all cases that require arigorous control of porosity, as, for example, with semi-permeablemembranes. Finally, it is also clear that the methodology is applicableto any type of porous bioceramic material.

1. A method to obtain a biocompatible polymer-ceramic composite materialof a predetermined porosity, said method comprising a first phase (a) ofthe production of a suspension of bioceramic material in distilledwater, wherein it also comprises a second phase (b) in which a compactof said bioceramic material containing a desired quantity of water isobtained from the suspension, said compact being then mixed in a thirdphase (c) with a polymeric material and/or with a liquid monomer;characterized in that said compact is obtained via sedimentation in acentrifuge.
 2. The method according to claim 1, characterized by thefact that the desired quantity of water is calculated on the basis of acombination of a calibration curve of the water contained in a compactof bioceramic material as a function of the different level ofcompaction through which the compact is obtained, and of a calibrationcurve of the porosity of a polymer-ceramic composite as a function ofthe quantity of water contained in the compact used in creating thepolymer-ceramic composite itself.
 3. Method according to any of thepreceding claims, characterized by the fact that the said polymericmaterial is a polymethyl methacrylate polymer, and that the said liquidmonomer is methyl methacrylate.
 4. Method according to claim 3,characterized by the fact that the said prepolymer and the monomer arepre-mixed to form a concentrated polydispersed suspension of sphericalparticles of prepolymer in the monomer.
 5. Method according to claim 3or 4, characterized by the fact that the said bioceramic material isconstituted of calcium-deficient hydroxyapatite.
 6. Method according toclaim 3 or 4, characterized by the fact that the said bioceranicmaterial is constituted of tricalcic-phosphate α.
 7. Method according toclaim 6, the preparation of said tricalcic-phosphate α comprises a finalrapid cooling phase and a sieving phase, possibly after grinding, inorder to collect particles of irregular shape approximately rangingbetween 1 and 10 μm in size.
 8. Method for predicting and designing theporosity of a biocompatible polymer-ceramic composite materialcharacterized by the fact that it includes the following phases: (a′)producing a suspension of a bioceramic material in distilled water; (b′)starting from identical volumetric quantities of initial suspension,obtaining from the suspension a series of compacts of the selectedbioceramic material containing different quantities of water; (c′)mixing each of said compacts obtained with an identical quantity of apolymeric material and/or a liquid monomer in order to obtain a porousgeometric solid of pre-defined dimensions; (d′) for each compact,calculating the porosity of the solid by obtained from it; and (e′)correlating said porosity with the compact's residual content in water.9. Method for predicting and designing the porosity of a biocompatiblepolymer-ceramic composite material according to claim 10, characterizedby the fact that the phase of obtaining said compacts, which havedifferent residual water contents, from said suspension, is performed bycentrifuging said pre-determined volumetric quantities of saidsuspensions at various, progressively increasing, accelerations.
 10. Amethod to obtain a biocompatible polymer-ceramic composite material of apredetermined porosity, said method comprising a phase (a) of theproduction of a suspension of bioceramic material in distilled water andbeing characterized by the fact that it also comprises a phase (b),wherein a compact of said bioceramic material containing a desiredquantity of water is obtained from the suspension, by compacting saidsuspension so as to obtain said compact and an aqueous phase and byseparating the aqueous phase from the compact, the method furtherincluding, in combination with phase (b) a phase (c) wherein saidcompact is mixed with a polymeric material and/or with a liquid monomer.11. The method of claim 11, wherein said stages of compacting saidsuspension so as to obtain said compact and an aqueous phase and ofseparating the aqueous phase from the compact are carried out viasedimentation in a centrifuge.
 12. Biocompatible polymer-ceramiccomposite having controlled porosity characterized in that it has beenobtained using calcium-deficient hydroxyapatite according to the methodof claim 1 or
 10. 13. Use of a calcium-deficient hydroxyapatite forobtaining a biocompatible polymer-ceramic composite having controlledporosity by forming a suspension of bioceramic material including saidcalcium-deficient hydroxyapatite in distilled water, and by obtaining acompact from said suspension consisting in said bioceramic material anddesired quantity of water and then mixing the compact with a polymericmaterial and/or with a liquid monomer.